Pöördumine

THE EUROPEAN DIRECTORATE FOR THE QUALITY OF MEDICINES & HEALTHCARE (EDQM)  SARE Reporting for Tissues and Cells SoHO Standard Section, Department of Biological Standardization, OMCL Network & HealthCare (DBO) EDQM, Council of Europe ©2023 EDQM, Council of Europe. All rights reserved. 2 Reporting countries 2022 SARE exercise (2021 data) 2021 DATA COLLECTED from 29* Countries: AT LV 2020 DATA BE LI COLLECTED BG LT from 28* HR LU Countries: CZ MT AT, BE, BG, DK NL HR, CZ, DK, EE NO EE, FI, FR, FI PL DE, EL, HU, FR PT IE, IT, LV, LT, DE RO LU, MT, NL, EL SI NO, PL, PT, HU ES RO, SK, SI, IE SE and ES, SE and IS UK (Northern UK. IT Ireland) *25 Member States + 4 Non-Member States ©2023 EDQM, Council of Europe. All rights reserved. 3 Incidence of replacement T&C 2021 (distributed and recipients pmp*) United Kingdom (UK)* 28 27 192 Incidence by Distributed T&C pmp Incidence by Recipients pmp Sweden (SE) 200 Spain (ES) 669 503 Slovenia (SI) 176 109 Romania (RO) 7 7 Portugal (PT) 115 129 Poland (PL) 622 36 Norway (NO) 187 170 Netherlands (NL) 4057 429 Malta (MT) 12 12 Lithuania (LT) 58 57 Ireland (IE) 146 143 Hungary (HU) 79 110 Greece (EL) 1409 845 France (FR) 1534 1137 Finland (FI) 656 320 Estonia (EE) 468 251 Denmark (DK) 568 409 Czechia (CZ) 856 16 Croatia (HR) 169 138 Bulgaria (BG) 106 83 Austria (AT) 979 109 -400 100 600 1100 1600 2100 2600 3100 3600 4100 population on January 1st 2021, https://ec.europa.eu/eurostat/web/population-demography/demography-population-stock-balance/database * https://www.nisra.gov.uk/publications/census-2021-table-lookups (Due to Brexit, UK= northern Ireland only) ©2023 EDQM, Council of Europe. All rights reserved. 4 Incidence of HSC 2021 (distributed and recipients pmp) United Kingdom (UK) 74 Sweden (SE) 106 Incidence by Distributed T&C pmp Incidence by Recipients pmp 86 Spain (ES) 77 76 Slovenia (SI) 301 65 Romania (RO) 19 15 Portugal (PT) 54 52 Poland (PL) 254 20 Netherlands (NL) 325 102 Lithuania (LT) 81 81 Italy (IT) 92 80 Ireland (IE) 165 149 Hungary (HU) 39 31 Greece (EL) 50 50 France (FR) 79 Finland (FI) 95 88 Denmark (DK) 209 88 Czechia (CZ) 141 82 Croatia (HR) 164 68 Bulgaria (BG) 23 22 Austria (AT) 219 126 -20 30 80 130 180 230 280 330 ©2023 EDQM, Council of Europe. All rights reserved. 5 Incidence of reproductive T&C 2021 (distributed and recipients pmp) Sweden (SE) 1,165 1996 Incidence by Distributed T&C pmp Incidence by Recipients pmp Slovenia (SI) 3522 2,377 Romania (RO) 536 536 Portugal (PT) 529 656 Netherlands (NL) 3863 1,778 Malta (MT) 595 595 Luxembourg (LU) 3099 1,574 Lithuania (LT) 763 763 Ireland (IE) 2191 1,460 Hungary (HU) 1032 94 Finland (FI) 1,247 Denmark (DK) 1131 3,049 Czechia (CZ) 8696 3,380 Croatia (HR) 2566 1,423 Bulgaria (BG) 9032 1,334 Austria (AT) 2309 1,212 -900 100 1,100 2,100 3,100 4,100 5,100 6,100 7,100 8,100 9,100 population on January 1st 2021, https://ec.europa.eu/eurostat/web/population-demography/demography-population-stock-balance/database * https://www.nisra.gov.uk/publications/census-2021-table-lookups (Due to Brexit, UK= Northern Ireland only) ©2023 EDQM, Council of Europe. All rights reserved. 6  2022 SARE Exercise (2021 data) Denominators ©2023 EDQM, Council of Europe. All rights reserved. 7  2022 SARE Exercise (2021 data) Denominators and total number of SAR by year (2010 - 2021) 500 2,133,341 2,102,332 460 450 1,990,000 400 350 350 1,490,453 326 1,490,000 307 300 1,314,512 1,165,510 1,192,203 1,116,519 250 246 1,000,693 231 238 991,538 995,407 221 990,000 200 203 190 711,061 150 156 138 490,000 100 377,023 365,060 333,253 361,418 340,582 321,618 300,857 318,467 245,058 209,243 50 177,538 111,025 0 -10,000 2010 2011 2012 2013 2014 2015 2016 2017 2018 2019 2020 2021 Number Distributed Number Recipients Total Number SAR ©2023 EDQM, Council of Europe. All rights reserved. 8 Denominators by Country 2022 SARE exercise (2021 data) Replacement T&C N= 391 687 (distributed)* TC Distributed TC Recipients 103,773 99,000 0 N= 132 176 (recipients)* 88,530 76,942 7,500 79,000 70,907 59,000 39,000 23,862 1,363 31,709 0 23,549 20,722 9,029 19,000 977 15,044 171 8,750 8,985 2,389 1,771 0 578 334 1,072 715 918 1,330 141 230 2,079 556 0 0 161 3,865 6 52 3,317 3,633 734 684 623 768 732 396 1,007 1,182 1,997 47 161 6 141 371 54 -1,000 Romania (RO) Finland (FI) Austria (AT) Bulgaria (BG) Malta (MT) Norway (NO) Spain (ES) Denmark (DK) Lithuania (LT) Portugal (PT) Slovenia (SI) Sweden (SE) Hungary (HU) Belgium (BE) Czechia (CZ) Estonia (EE) France (FR) Ireland (IE) Italy (IT) Poland (PL) United Kingdom (UK) Croatia (HR) Germany (DE) Greece (EL) Latvia (LV) Netherlands (NL) Luxembourg (LU) *Data set was incomplete or not available at the time of reporting (BE, IT, IS, LV, LU), or is not collected (DE). ©2023 EDQM, Council of Europe. All rights reserved. 9 Denominators by Country 2022 SARE exercise (2021 data) Hematopoietic Stem Cells (HSC) N= 38 597 (distributed)* 12,000 TC Distributed TC Recipients N = 23 423 (recipients)* 10,000 9,619 8,000 6,000 5,682 5,319 5,463 4,731 3,620 4,000 3,632 3,221 1,961 1,783 2,000 1,476 895 1,124 1,220 1,104 862 824 747 747 664 513 526 489 533 533 377 555 539 634 273 251 303 227 227 359 285 0 158 154 0 0 0 0 111 0 138 0 141 0 *Data set was incomplete or not available at the time of reporting (BE, EE, FR, LV, LT, LU, MT, NO, ES, UK), or is not collected (DE). ©2023 EDQM, Council of Europe. All rights reserved. 10  2022 SARE exercise (2021 data) Reproductive T&C N= 761 919 (distributed)* 300,000 278,051 TC Distributed TC Recipients N= 162 868 (recipients)* 250,000 200,000 150,000 142,759 100,000 91,262 67,507 62,472 50,000 35,468 31,069 20,626 20,720 2,132 6,758 10,298 10,826 10,356 17,806 10,970 999 5,014 10,040 10,298 12,093 9,224 5,744 6,607 6,903 7,311 9,073 5,450 7,427 869 916 11 3,015 2,132 1,967 307307 0 *Data set was incomplete at the time of reporting (BE, DE, FI, LI, LV, LT, NO), was not available (EE, EL, FR, IT, IS, PL, ES, UK) or is not collected (DE). ©2023 EDQM, Council of Europe. All rights reserved. 11  2022 SARE exercise (2021 data) Denominators: reporting countries Cardiovascular Skeletal Tissues Ocular Tissues Skin Other Tissues 23 18 24 18 10 (AT, BE, BG, HR, CZ, (AT, BE, HR, CZ, EE, (AT, BE, BG, HR, CZ, (AT, BE, BG, HR, Distributed (AT, HR, CZ, DK, EE, FI, FR, DE, FI, FR, DE, HU, IE, DK, EE, FI, FR, DE, CZ, DK, EE, FI, FR, T&C FI, EL, NL, EL, HU, IE, LT, LU, NL, IT, LU, NL, PL, PT, SI, EL, HU, IE, LT, LV, MT, DE, EL, LT, LU, NL, NO, PL, SI NO, PL, PT, SI, ES, SE ES and SE) NL, NO, PL, PT, RO, NO, PL, SI, and and SE) and UK) SI, ES, and SE) SE) 19 13 20 9 14 (AT, BG, HR, DK, EE, (AT, HR, CZ, DK, EE, (AT, BG, HR, EE, FI, (AT, HR, FI, (AT, BG, HR, CZ, Recipients FI, FR, EL, HU, IE, LT, FI, FR, HU, IE, NL, FR, DE, EL, HU, IE, LT, FR, EL, NL, DK, EE, FI, FR, EL, NL, NO, RO, PT, SI, PT, SI, ES and SE) MT, NL, NO, PL, PT, NO, ES, and LT, NL, NO, SI, and ES, SE and UK) RO, SI, ES, and SE) SE) SE) ©2023 EDQM, Council of Europe. All rights reserved. 12 Replacement T&C 2022 SARE exercise (2021 data) NUMBER OF DISTRIBUTED T&C BY SUB-CATEGORY N= 391 687 Other tissues or Skin cells 22,313 20,413 6% Cardiovascular tissues 5% 6,430 2% Ocular tissues 30,858 8% Skeletal tissues 311,673 79% ©2023 EDQM, Council of Europe. All rights reserved. 13  2022 SARE exercise (2021 data) N= 311 673 Distributed Skeletal Tissues by Type Bone 263,439 General skeletal 28,635 tissues Tendons/ligaments 6,203 Fascia 5,925 Other (e.g. meniscus, 3,883 ear, ossicles) Cartilage 3,588 0 50,000 100,000 150,000 200,000 250,000 300,000 General skeletal tissues : EE, LT, NO, PT, and ES ©2023 EDQM, Council of Europe. All rights reserved. 14  2022 SARE exercise (2021 data) N= 30 858 N= 6 430 Distributed ocular tissues by type Distributed cardiovascular tissues by type Cornea 26,352 Vessel 4,444 Sclera 2,553 Heart valve 1,508 General Other CV tissues 1,953 (e.g. conduit, patch or 362 ocular tissue pericardium) Other 0 General CV 116 0 5,000 10,000 15,000 20,000 25,000 30,000 0 1,000 2,000 3,000 4,000 5,000 General ocular tissues : AT, CZ, LV, LT, and NO General cardiovascular tissues : LT and NO ©2023 EDQM, Council of Europe. All rights reserved. 15  2022 SARE exercise (2021 data) N= 22 313 N= 20 413 Distributed Other Replacement T&C by type Skin units in cm2 are not included in the total: Country Processed (cm²) Distributed (cm²) Amniotic membrane 16,908 Belgium 209,557 France Other (e.g. adipose tissue, N/A 380,000 4,157 tympanic membrane ) Germany 126,748 150,067 Spain Pancreatic islets 1,248 860,364 419,294 Hepatocytes 0 0 4,000 8,000 12,000 16,000 20,000 ©2023 EDQM, Council of Europe. All rights reserved. 16  2022 SARE exercise (2021 data) Denominators: reporting countries General Bone Marrow PBSC Cord Blood DLI Other HPC 17 15 13 4 8 (AT, BE, BG, DK, 6 Distributed (AT, BE, BG, DK, HR, EE, HR, FI, EL, IE, (AT, BE, CZ, (HU, LT, (BE, EL, FI, IE, T&C CZ, EE, FI, EL, IE, IT, NL, PL, PT, RO DK, HR, EL, FI, (BE, HR, GR NO and IT, NL, PL, and IT, NL, PL, PT, RO, and SE) IT, NL, PL, PT, and PL) ES) SI) SI, and SE) RO and SE) 18 15 12 6 3 (AT, BE, BG, DK, FR, (AT, BG, DK, HR, 4 (AT, CZ, DK, Recipients (HU, LT HR, CZ, EE, FI, EL, FI, FR, EL, IE, IT, (FR, EL, IT, NL HR, EL, FI, FR, and ES) IE, IT, NL, PL, PT, NL, PL, PT, RO, SE (HR and GR) SE and SI) IE, IT, NL, SE RO, SI, and SE) and UK) and UK) ©2023 EDQM, Council of Europe. All rights reserved. 17 Hematopoietic Stem Cells 2022 SARE exercise (2021 data) NUMBER OF DISTRIBUTED T&C BY SUB-CATEGORY N= 38 597 Bone Marrow (auto+allo) Other Haematopoietic Stem Cells 1,846 (units) 559 5% Donor Lymphocyte Infusions 1% 1,867 5% Cord Blood 2,604 7% General HPC Peripheral Blood Stem 4,347 Cells (auto+allo) 11% 27,374 71% ©2023 EDQM, Council of Europe. All rights reserved. 18 Hematopoietic Stem Cells 2022 SARE exercise (2021 data) N= 27 374 Distributed Peripheral Blood Stem Cells by type Autologous 12,194 General 10,721 Allogenic unrelated 2,789 Allogenic related 1,670 0 2,000 4,000 6,000 8,000 10,000 12,000 14,000 ©2023 EDQM, Council of Europe. All rights reserved. 19 Hematopoietic Stem Cells 2022 SARE exercise (2021 data) N= 1 846 N= 2 604 Distributed Cord Blood Cells by type General 2,523 Allogenic unrelated 75 Allogenic related 5 Autologous 1 0 500 1,000 1,500 2,000 2,500 3,000 ©2023 EDQM, Council of Europe. All rights reserved. 20 Hematopoietic Stem Cells 2022 SARE exercise (2021 data) N= 1 867 N= 559 Distributed Donor Lymphocyte Infusions by type Distributed Other HSC General 1,089 General 464 Allogenic unrelated 95 Allogenic unrelated 418 Allogenic related 0 Allogenic related 360 Autologous 0 0 200 400 600 800 1,000 1,200 0 50 100 150 200 250 300 350 400 450 500 ©2023 EDQM, Council of Europe. All rights reserved. 21  2022 SARE exercise (2021 data) Denominators: reporting countries Embryos Sperm Other Reproductive 18 18 7 (AT, BE, BG, HR, DE, DK, HU, IE, Distributed T&C (AT, BE, BG, HR, CZ, FI, HU, LI, LT, LU, LV, MT, NL, NO, RO, (AT, BE, CZ, DK, DE, NL, IE, LT, LU, LV, MT, NL, NO, PT, SI, and SE) and SI) RO, SI, and SE) 16 14 6 (AT, BG, HR, CZ, DK, HU, FI, IE, Recipients (AT, BG, HR, CZ, DK, HU, IE, LT, LU, MT, NL, PT, RO, SI, and LT, MT, NL, PT, RO, SI, and SE) (AT, CZ, DK, NL, SI and SE) SE) ©2023 EDQM, Council of Europe. All rights reserved. 22 Denominators for Reproductive T&C 2022 SARE exercise (2021 data) 1,980,000 250 Number Distributed Number Recipients Number SAR 1,779,943 1,787,524 1,800,000 211 1,620,000 200 1,440,000 181 172 1,260,000 148 150 150 1,080,000 131 966,690 124 900,000 835,060 786,451 761,919 738,282 100 720,000 670,565 596,244 81 79 540,000 477,684 494,304 50 360,000 245,849 255,748 228,771 223,647 216,157 29 187,511 162,868 180,000 114,568 142,197 100,598 110,816 15 0 0 2011 2012 2013 2014 2015 2016 2017 2018 2019 2020 2021 # SAR 13 countries: BE, HR, CZ, DK, EE, FI, IE, IT, NO, PT, ES, SE and UK ©2023 EDQM, Council of Europe. All rights reserved. 23 Reproductive T&C 2022 SARE exercise (2021 data) NUMBER OF DISTRIBUTED T&C BY SUB-CATEGORY N= 761 919 Testicular tissue (2,465) Ovarian tissue (183) 0% 0% Sperm (234,661) 31% Embryo (524,610) 69% ©2023 EDQM, Council of Europe. All rights reserved. 24  2022 SARE exercise (2021 data) NUMBER OF DISTRIBUTED EMBRYOS PER TYPE NUMBER OF DISTRIBUTED SPERM PER TYPE N= 524 610 N= 234 661 Embryo donor oocyte, partner sperm (24,710) Embryo donor sperm and Sperm non-partner donation (30,401) 5% oocyte (33,270) 13% 6% Embryo donor sperm, partner oocyte (8,082) 2% Sperm partner donation (55,181) Embryo general (275,496) Embryo partner Sperm general (149,079) 23% 52% gametes (183,052) 64% 35% ©2023 EDQM, Council of Europe. All rights reserved. 25  2022 SARE Exercise (2021 data) SAR in Recipients ©2023 EDQM, Council of Europe. All rights reserved. 26 SAR Incidence 2022 SARE exercise (2021 data) Incidence of SAR by Country for Replacement T&C Incidence of SAR / 10000 recipients 250 Number of Country Number of Incidence of SAR / SAR 217 Recipients 10 000 recipients Denmark (DK) 685 2 29 200 France (FR) 10 738 18 17 Greece (EL) 328 3 91 Ireland (IE) 46 1 217 150 Netherlands (NL) 1 591 1 6 Portugal (PT) 931 1 11 91 100 Spain (ES) 23 753 11 5 50 29 Number of TC Incidence of SAR / 17 T&C Number of SAR 11 recipients 10 000 recipients 6 5 0 Replacement T&C 38 072 37 10 Note: SAR from countries that did not report the number of recipients, were not considered. ©2023 EDQM, Council of Europe. All rights reserved. 27 SAR Incidence 2022 SARE exercise (2021 data) Incidence of SAR by Country for HSC Incidence of SAR / 10 000 recipients Number of Number of 450 Country Recipients Incidence of SAR / SAR 10 000 recipients 400 391 Austria (AT) 329 3 91 350 France (FR) 4 971 46 92 333 300 Greece (EL) 358 14 391 Ireland (IE) 676 2 29 250 Netherlands (NL) 30 1 333 200 Poland (PL) 747 7 94 Spain (ES) 3 620 4 11 150 100 91 92 94 Number of TC Incidence of SAR / T&C Number of SAR 50 recipients 10 000 recipients 29 Hematopoietic Stem 0 11 10 731 77 72 Cells Note: SAR from countries that did not report the number of recipients, were not considered. ©2023 EDQM, Council of Europe. All rights reserved. 28 SAR Incidence 2022 SARE exercise (2021 data) Incidence of SAR by Country for Reproductive T&C Incidence of SAR / 10 000 recipients Number of 100 Country Number of Incidence of SAR / SAR 93 Recipients 10000 recipients 90 Croatia (HR) 5 744 5 9 Czechia (CZ) 29 064 14 5 80 Denmark (DK) 4 511 29 64 70 Ireland (IE) 321 3 93 64 Portugal (PT) 3 205 6 19 60 50 Number of TC Number of Incidence of SAR T&C recipients SAR /10 000 recipients 40 Reproductive T&C 42 845 57 13 30 20 19 10 9 5 0 Croatia (HR) Czechia (CZ) Denmark (DK) Ireland (IE) Portugal (PT) Note: SAR from countries that did not report the number of recipients, were not considered. ©2023 EDQM, Council of Europe. All rights reserved. 29 SAR Globally Total SAR in Recipients by Country in 2021 70 64 60 53 53 50 40 31 30 23 24 20 17 14 10 6 7 7 5 5 4 5 3 2 2 1 0 ©2023 EDQM, Council of Europe. All rights reserved. 30 SAR Globally SAR per country and category of T&C 0 10 20 30 40 50 60 70 Austria (AT) 3 Belgium (BE) 2 5 7 5 Croatia (HR) 53 Czechia (CZ) 2 29 Denmark (DK) 1 Estonia (EE) 5 Finland (FI) France (FR) 18 46 Germany (DE) 18 5 Greece (EL) 3 14 Ireland (IE) 1 2 3 1 1 Italy (IT) 1 1 Netherlands (NL) 24 Norway (NO) Poland (PL) 7 1 6 Portugal (PT) Spain (ES) 11 4 38 4 Sweden (SE) 5 United Kingdom (UK) Replacement TC Haematopoietic TC Reproductive TC ©2023 EDQM, Council of Europe. All rights reserved. 31  2022 SARE exercise (2021 data) Number of SAR per sub-category of T&C N = 58 Other tissues or cells (11) 19% Skeletal tissues (15) 26% Skin (1) 2% Cardiovascular tissues (3) 5% Ocular Tissues (28) 48% ©2023 EDQM, Council of Europe. All rights reserved. 32  2022 SARE exercise (2021 data) N = 58 Replacement Tissues& Cells T&C Sub-Type SAR Skeletal tissues Bone 10 Tendons/ligaments 2 Cartilage 2 General skeletal tissues 1 Ocular tissues Cornea 28 Cardiovascular tissues Heart valve 1 Vessel 2 Skin Skin 1 Other tissues or cells Amniotic membrane 11 ©2023 EDQM, Council of Europe. All rights reserved. 33 Replacement T&C 2022 SARE exercise (2021 data) Distribution of SAR by Type of Reaction N = 58 0 5 10 15 20 25 Transmitted infections Bacterial (5) 4 1 Viral other (2) 2 Fungal (4) 4 Immunological reactions (3) 3 Other SAR Graft failure/delayed (28) 14 12 1 1 Undue exposure risk interv (3) 1 1 1 Others (13) 2 11 Skeletal tissues Ocular Tissues Cardiovascular Tissues Skin Other tissues or cells ©2023 EDQM, Council of Europe. All rights reserved. 34 Replacement T&C 2022 SARE exercise (2021 data) SAR Type 1 Transmitted Infections (11) • - Endophthalmitis / Enterococcus faecium infection (DE) - Sclerokeratitis. Suspicion of infection in the sclera. Scleral patch removal Ocular tissues and microbiological culture. (ES) Bacterial • - Eye removed (DK) Cardiovascular •- Surgical wound Infection (cryopreserved vascular graft) (ES) Tissues - Herpes infection in left cornea: Both the storage and transport medium tested positive for herpes simplex. No contamination seen on Viral other Ocular tissues slit lamp examination. The other cornea tested negative (BE) - Herpetic uveitis. Satisfactory evolution. (ES) - Transplant removed (DK) - Candida albicans ocular infection (DE) Fungal Ocular tissues - Candida glabrata (NL) - 1. Fungal keratitis caused by Exophiala. 2. Corneal fungal infection (Candida albicans). (ES) ©2023 EDQM, Council of Europe. All rights reserved. 35 Replacement T&C 2022 SARE exercise (2021 data) SAR Type 4 Other SAR (47) Graft failure / delayed Undue exposure to risk- Immunological engraftment (28) intervention (3) Other reactions (13) reaction (3) • Bone block non-integration, • Graft opacity five days after • Corneal pannus (11) inflammation implantation possibly due to a • Graft failure • Graft dissolution & explantation decrease in endothelial quality • Post graft corneal striae • Refixation necessary due to prolonged storage, taking • Slow clearance of corneal • Incorrect retrieval procedure (too into account the initial quality edema. Small tear 0.2mm in the much traction) and excessive handling to obtain descemet membrane transplant • Unexpected graft non absorption the DSAEKlamella; lamella at the hinge occurring / reabsorption reimplantation. during preparation. Package • Graft failure due to poor dropped; outer and inner condition; graft folded on itself • Perforated internal and external packaging intact, donor cornea still with peripheral damage; bags noticed after patient was suspended from floating device. retransplantation anesthetised; procedure not Upon inspection perioperatively, • Primary graft failure (corneal performed; calota resubmitted the entire descemet membrane edema after cataract surgery); for further processing. graft lamella appeared loose in the retransplantation (micro explant transport medium rather than • Valve missized; issue discovered attached to the hinge envelope. negative) in the operating theatre; valve Surgery could continue to perform • Primary graft failure (DMEKbent could not be used. empty artis. Postoperatively graft and damaged in the central area) not abutted; rebubbling performed. • Cornea guttata; graft failure ©2023 EDQM, Council of Europe. All rights reserved. 36 Hematopoietic Stem Cells 2022 SARE exercise (2021 data) N = 87 NUMBER OF SAR PER SUB-CATEGORY OF T&C Cord blood (3) General HPC (4) 3% 5% Bone marrow (auto+allo) (19) 22% Peripheral blood progenitor cells (auto+allo) (61) 70% ©2023 EDQM, Council of Europe. All rights reserved. 37  2022 SARE exercise (2021 data) Distribution of SAR by Type of Reaction N = 87 0 5 10 15 20 25 30 35 Transmitted infections Fungal Infection (1) 1 Cardiovascular reactions (1) 1 Pulmonary reactions (4) 1 3 Neurological reactions (3) 3 Other SAR Toxicity (3) 2 1 Immunological reactions (17) 2 4 11 Graft failure/delayed (35) 12 22 1 Infusion related non specific symptoms (7) 1 6 Other (15) 2 12 1 Other Disease Transmissions Immunological disease (1) 1 General HPC Bone marrow Peripheral blood progenitor cells Cord blood ©2023 EDQM, Council of Europe. All rights reserved. 38  2022 SARE exercise (2021 data) HSC Category HSC Type SAR Bone marrow Allogenic related 8 Allogenic unrelated 5 General 6 Cord blood Allogenic related 3 Peripheral blood progenitor cells Allogenic related 10 Allogenic unrelated 31 Autologous 7 General 13 General HPC 4 ©2023 EDQM, Council of Europe. All rights reserved. 39  2022 SARE exercise (2021 data) HSC Sub-type Allogenic Allogenic Autologous General Type of SAR Sub-type of SAR HSC Type Related Unrelated Transmitted infections (1) Fungal infection (Candida PBSC (1) 1 glabrata) (1) Other disease transmission (1) Immunological reaction PBSC (1) 1 (anaphylactic shock) (1) Other SAR (85) Graft failure/delayed Bone marrow (12) 6 3 3 engraftment (35) Cord blood (1) 1 PBSC (23) 4 14 1 3 Immunological reactions (17) Bone marrow (4) 2 1 1 General HSC (1) PBSC (11) 4 6 1 Infusion related non-specific Bone marrow (1) 1 symptoms (7) PBSC (6) 1 2 3 Pulmonary reactions (4) General HSC (1) PBSC (3) 3 Neurological reactions (3) PBSC (3) 1 2 Cardiovascular reaction (1) Bone marrow (1) 1 Toxicity (3) Cord blood (1) 1 PBSC (2) 1 1 Others (15) Bone marrow (2) 1 1 Cord blood (1) 1 General HSC (1) PBSC (11) 1 3 1 6 ©2023 EDQM, Council of Europe. All rights reserved. 40  2022 SARE exercise (2021 data) SAR Type 1 Transmitted infections SAR Type 4 Other SAR Fungal infection caused by Candida • Death 3 months post-transplant without identified cause glabrata (peripheral blood stem cells) • Death by septic shock • Immunological reactions • Infusion related non-specific symptoms • Cardiovascular reactions • Neurological reactions SAR Type 2 Malignant diseases • Pulmonary reactions None reported in 2021 • Toxicity • Graft failure/delayed engraftment • Primo infection with Epstein barr virus • Epstein-Barr virus associated lymphoma SAR Type 3 Other disease • Non-infectious febrile reaction • Reactions other than those listed above transmission • Febrile reaction 1 hour after infusion Immunological reactions – anaphylactic • Suspected TRALI, multi-organ failure shock (allogenic unrelated PBSC) • Veno-occlusive disease • Septic shock; Aspergillus infection • Seizure • Blood extravasation suspected at the end of the apheresis of peripheral blood progenitor cells for own use; no dyspnea and vital signs maintained • Death of recipient within 30 days after transplantation or during the first hospitalisation in connection with transplantation ©2023 EDQM, Council of Europe. All rights reserved. 41  2022 SARE exercise (2021 data) NUMBER OF SAR PER CATEGORY OF T&C N = 181 Ovarian tissue (0) 0% Sperm (62) 34% Embryo (119) 66% ©2023 EDQM, Council of Europe. All rights reserved. 42  2022 SARE exercise (2021 data) N = 181 Reproductive T&C Sub-Type SAR # SAR % Tissues & Cells EMBRYO Donor oocyte, partner sperm 50 28 Donor sperm and oocyte 15 8 Donor sperm, partner oocyte 17 9 Partner gametes 29 16 General 8 4 SPERM Non-partner donation 56 31 Partner donation 6 3 ©2023 EDQM, Council of Europe. All rights reserved. 43  2022 SARE exercise (2021 data) SAR Types in Embryos N = 119 Pneumonia (1) 1 Bacterial infection 3 ovaries (3) Pregnancy of unknown origin (1) 1 Molar pregnancy (1) 1 Ectopic pregnancy (30) 3 1 3 23 Transmitted Genetic Conditions (83) 46 14 14 5 4 0 10 20 30 40 50 60 70 80 Donor oocyte, partner sperm Donor sperm and oocyte Donor sperm, partner oocyte Partner gametes General Embryos ©2023 EDQM, Council of Europe. All rights reserved. 44  2022 SARE exercise (2021 data) SAR Types in Sperm N = 62 0 5 10 15 20 Transmitted Genetic Conditions (24) 24 Ectopic pregnancy (7) 1 6 Other disease transmission (13) 13 Anaphylactic reaction (7) 7 Other SAR (11) 11 Sperm Non-partner donation (56) Sperm Partner donation (6) ©2023 EDQM, Council of Europe. All rights reserved. 45  2022 SARE exercise (2021 data) Transmitted genetic conditions Other SAR Other disease transmission •Autism spectrum disorder •Bilateral hearing impairment • Ectopic pregnancy (requiring • c.985A>G mutation of the ACADM •Hypotonia, lax joints and motor development issues surgical intervention or gene in the homozygous state •Cataract hospitalization) • Alpha-1 Anti-trypsin deficiency •One kidney •Downs syndrome • Pregnancy of unknown origin • Spina bifida •Noonan Syndrome • Anaphylactic reactions • X – linked hypophosphatemia with •Extra chromosome •Encephalocele • Molar pregnancy vitamin D resistant rickets. •Heterozygous mutation • Bacterial infection ovaries & tubes Mutations PHEX gene on Xp22.0 •Factor-V-Leyden, increased risk of blood clotting • Germline mutation •Ocular albinism • Pneumonia •Susceptibility to PTEN hamartoma • Deafness • Rasopathy •Craniosynostosis detected during pregnancy •Autism, Hirschsprung syndrome, dysmorphic features •16p11.2 microduplication •G6PD deficiency sumptoms •Multiple epiphyseal dysplasia •Nephotic Syndrome symptoms •Polyendocrinopathy autoinmune (autosomal recessive) •Exostosis •Fucosidosis (autosomal recessive) •Hemophagocytosis •Mucolipidosis type II •Spinal muscular atrophy •Mitochondrial Depletion Syndrome •Spina bifida (Voluntary termination of pregnancy) ©2023 EDQM, Council of Europe. All rights reserved. 46  2022 SARE exercise (2021 data) SAR Imputability ©2023 EDQM, Council of Europe. All rights reserved. 47  2022 SARE exercise (2021 data) Imputability Reporting Rate in 2021 SAR with imputability Imputability Total number of reported Level T&C Category SAR in 2021 # % IL1 IL2 IL3 Replacement T&C 58 41 12 27 7 7 HSC 87 65 20 41 14 10 Reproductive T&C 181 9 3 7 2 Total 326 115 35 75 21 19 ©2023 EDQM, Council of Europe. All rights reserved. 48  2022 SARE exercise (2021 data) Imputability for Replacement T&C SAR Type SAR Subtype IL1 IL2 IL3 Skeletal tissues Bone SAR Type - 4. Other SAR Other SAR: Graft failure/delayed engraftment 10 Cartilage SAR Type - 4. Other SAR Other SAR: Graft failure/delayed engraftment 2 Tendons/Ligaments SAR Type - 4. Other SAR Other SAR: Graft failure/delayed engraftment 2 General SAR Type - 4. Other SAR Other SAR: Undue exposure to risk-intervention 1 Cardiovascular Tissues Heart SAR Type - 4. Other SAR Other SAR: Undue exposure to risk-intervention 1 Vessel SAR Type - 1. Transmitted infections Bacterial 1 Ocular Tissues Cornea SAR Type - 1. Transmitted infections Bacterial 1 SAR Type - 1. Transmitted infections Fungal 1 SAR Type - 4. Other SAR Other SAR: Graft failure/delayed engraftment 2 1 SAR Type - 4. Other SAR Other SAR: Immunological reactions 3 SAR Type - 4. Other SAR Other SAR: Reactions other than those listed above 1 SAR Type - 1. Transmitted infections Bacterial 2 SAR Type - 1. Transmitted infections Fungal 1 SAR Type - 1. Transmitted infections Fungal 1 SAR Type - 1. Transmitted infections Bacterial 1 SAR Type - 1. Transmitted infections Fungal 1 1 SAR Type - 1. Transmitted infections Viral : Other 1 SAR Type - 4. Other SAR Other SAR: Graft failure/delayed engraftment 1 1 2 SAR Type - 4. Other SAR Other SAR: Undue exposure to risk-intervention 1 Other T/C Amniotic Membrane SAR Type - 4. Other SAR Other SAR: Reactions other than those listed above 1 Skin SAR Type - 4. Other SAR Other SAR: Graft failure/delayed engraftment 1 Total Replacement T&C 41 27 7 7 ©2023 EDQM, Council of Europe. All rights reserved. 49 Imputability for HSC 2022 SARE exercise (2021 data) Bone Marrow SAR Type SAR Sub-type IL1 IL2 IL3 Allogenic Related SAR Type - 4. Other SAR Other SAR: Graft failure/delayed engraftment 5 1 SAR Type - 4. Other SAR Other SAR: Immunological reactions 2 Allogenic Unrelated SAR Type - 4. Other SAR Other SAR: Graft failure/delayed engraftment 2 1 SAR Type - 4. Other SAR Other SAR: Immunological reactions 1 SAR Type - 4. Other SAR Other SAR: Reactions other than those listed above 1 Autologous SAR Type - 4. Other SAR Other SAR: Infusion related non-specific symptoms 1 SAR Type - 4. Other SAR Other SAR: Reactions other than those listed above 1 SAR Type - 4. Other SAR Other SAR: Immunological reactions 1 SAR Type - 4. Other SAR Other SAR: Graft failure/delayed engraftment 3 Cord Blood Allogenic Unrelated SAR Type - 4. Other SAR Other SAR: Graft failure/delayed engraftment 1 SAR Type - 4. Other SAR Other SAR: Toxicity (e.g. due to DMSO) 1 General HSC SAR Type - 4. Other SAR Other SAR: Immunological reactions 2 SAR Type - 4. Other SAR Other SAR: Pulmonary reactions 1 SAR Type - 4. Other SAR Other SAR: Reactions other than those listed above 1 Peripheral Blood Stem Cells Allogenic Related SAR Type - 4. Other SAR Other SAR: Immunological reactions 1 SAR Type - 4. Other SAR Other SAR: Graft failure/delayed engraftment 3 1 SAR Type - 4. Other SAR Other SAR: Immunological reactions 1 1 1 SAR Type - 4. Other SAR Other SAR: Neurological reactions 1 SAR Type - 4. Other SAR Other SAR: Reactions other than those listed above 1 SAR Type - 3. Other disease Allogenic Unrelated transmissions Immunological disease 1 SAR Type - 4. Other SAR Other SAR: Reactions other than those listed above 1 SAR Type - 4. Other SAR Other SAR: Graft failure/delayed engraftment 5 2 1 SAR Type - 4. Other SAR Other SAR: Immunological reactions 3 2 1 SAR Type - 4. Other SAR Other SAR: Reactions other than those listed above 2 Autologous SAR Type - 4. Other SAR Other SAR: Graft failure/delayed engraftment 1 SAR Type - 4. Other SAR Other SAR: Immunological reactions 1 SAR Type - 4. Other SAR Other SAR: Infusion related non-specific symptoms 2 General SAR Type - 4. Other SAR Other SAR: Infusion related non-specific symptoms 1 1 SAR Type - 4. Other SAR Other SAR: Reactions other than those listed above 1 SAR Type - 4. Other SAR Other SAR: Toxicity (e.g. due to DMSO) 1 SAR Type - 4. Other SAR Other SAR: Graft failure/delayed engraftment 1 SAR Type - 4. Other SAR ©2023 EDQM, Council of Europe. All rights reserved. 50 Other SAR: Reactions other than those listed above 3 Total HSC 65 41 14 10 Imputability for Reproductive T&C 2022 SARE exercise (2021 data) SAR Type SAR Subtype IL1 IL2 IL3 Embryos Embryos, donor oocyte, partner SAR Type - 3. Transmitted genetic sperm conditions 1 Embryos, donor sperm, partner SAR Type - 3. Transmitted genetic oocyte conditions 1 1 Other SAR: Ectopic pregnancy (requiring surgical Embryos, partner gametes SAR Type - 4. Other SAR intervention or hospitalization) 4 SAR Type - 3. Transmitted genetic General embryos conditions 1 Sperm Other SAR: Ectopic pregnancy (requiring surgical Sperm - partner donation SAR Type - 4. Other SAR intervention or hospitalization) 1 Total Reproductive T&C 9 7 2 ©2023 EDQM, Council of Europe. All rights reserved. 51  2022 SARE exercise (2021 data) Serious Adverse Events ©2023 EDQM, Council of Europe. All rights reserved. 52  2022 SARE exercise (2021 data) 3500000 1000 949 910 3,159,362 900 3000000 2,922,117 739 769 756 800 2,584,557 694 622 2500000 2,443,564 700 2,280,512 551 600 2000000 1,862,293 499 441 1,775,082 500 426 1,550,701 1500000 1,433,828 400 300 1000000 887,536 748,753 200 500000 100 0 0 2011 2012 2013 2014 2015 2016 2017 2018 2019 2020 2021 YEAR Tissues Processed Number SAE ©2023 EDQM, Council of Europe. All rights reserved. 53  2022 SARE exercise (2021 data) Processed T&C by Country and Category Variation in number of T&C Processed Country Replacement T&C HSC Reproductive T&C Country Exercise 2022 Exercise 2021 Exercise 2020 2021-2020 2021-2022 Austria (AT) 66,786 2,856 139,062 Austria 208,704 196,948 208,545 -11,597 11,756 Belgium (BE) 22,529 3,134 462,323 Belgium 487,986 0 0 0 487,986 Bulgaria (BG) 667 774 128,270 Bulgaria 129,711 118,546 126,876 -8,330 11,165 Croatia (HR) 1,045 1,602 51,507 Croatia 54,154 50,690 62,585 -11,895 3,464 Czechia (CZ) 11,104 2,209 377,585 Czechia 390,898 397,423 422,543 -25,120 -6,525 Denmark (DK) 1,452 896 49,627 Denmark 51,975 45,174 132,763 -87,589 6,801 Estonia (EE) 796 367 Estonia 1,163 34,838 40,766 -5,928 -33,675 Finland (FI) 2,845 1,018 Finland 3,863 4,515 6,119 -1,604 -652 France (FR) France 0 0 0 0 0 Germany (DE) 159,566 870,300 Germany 1,029,866 1,002,175 856,324 145,851 27,691 Greece (EL) 1 Greece 1 28 45 -17 -27 Hungary (HU) 1,226 457 25,590 Hungary 27,273 39,359 43,524 -4,165 -12,086 Ireland (IE) 469 434 102,932 Ireland 103,835 71,763 83,451 -11,688 32,072 Italy (IT) 8,996 6,023 Italy 15,019 15,876 44,093 -28,217 -857 Liechtenstein (LI) 197 Latvia 31,912 29,514 40,089 -10,575 2,398 Latvia (LV) 38 94 31,780 Liechtenstein 197 0 0 0 197 Lithuania (LT) Lithuania 0 2,795 19,165 -16,370 -2,795 Luxembourg (LU) 3,865 2,546 Luxemborug 6,411 1,770 2,112 -342 4,641 Malta (MT) 6 795 Malta 801 1,820 807 1,013 -1,019 Netherlands (NL) 12,670 245,607 Netherlands 261,382 222,020 248,064 -26,044 39,362 Norway (NO) 3,105 Poland (PL) 46,367 31,040 Norway 0 0 66,072 -66,072 0 Portugal (PT) 711 10,686 Poland 77,407 78,645 55,585 23,060 -1,238 Romania (RO) 15 4,770 Portugal 11,397 92,818 113,424 -20,606 -81,421 Slovenia (SI) 333 1,295 34,306 Romania 4,785 1,893 10,658 -8,765 2,892 Spain (ES) 29,251 Slovakia 13,651 -13,651 0 Sweden (SE) 3,459 1,795 190,052 Slovenia 35,934 27,627 74,904 -47,277 8,307 United Kingdom (UK) 131 Spain 29,251 26,888 5,802 21,086 2,363 Total 373,486 57,941 2,727,935 Sweden 195,306 77,083 244,150 -167,067 118,223 Total 3,159,362 2,646,079 2,922,117 -276,038 513,283 ©2023 EDQM, Council of Europe. All rights reserved. 54 SAE Incidence 2022 SARE exercise (2021 data) Incidence of SAE by Country for Replacement T&C Incidence of SAE / 10 000 T&C processed Number of T&C Incidence of SAE Country # SAE / 10 000 T&C Processed 22 processed 20 Austria (AT) 66,786 5 0.75 17 Belgium (BE) 22,529 32 14.2 France (FR) 103,773 17 1.6 Germany (DE) 15,9566 9 0.56 12 Hungary (HU) 1,226 55 9 Italy (IT) 8,996 10 11 Netherlands (NL) 12,670 6 5 7 Poland (PL) 46,367 1 0.2 Spain (ES) 29,251 27 9 Sweden (SE) 3,459 7 20 3.72 2 Incidence of SAE 0.2 Number of T&C Country # SAE / 10 000 T&C 0 1 2 3 4 5 6 7 8 9 10 Processed processed -3 All Reporting Countries 454,623 169 3.72 Incidence by Country Incidence Globally Note: SAE from countries that did not report the number of T&C processed, were not considered. ©2023 EDQM, Council of Europe. All rights reserved. 55 SAE Incidence 2022 SARE exercise (2021 data) Incidence of SAE by Country for HSC Incidence of SAE / Country # Processed # SAE 10 000 T&C Incidence of SAE / 10 000 T&C processed processed 600 Austria (AT) 2,856 3 10 Belgium (BE) 3,134 17 54 Bulgaria (BG) 774 3 39 500 Croatia (HR) 1,602 3 19 478 Czechia (CZ) 2,209 2 9 Finland (FI) 1,018 5 49 400 Ireland (IE) 434 8 184 Italy (IT) 6,023 11 18 300 Netherlands (NL) 3,105 3 10 Poland (PL) 31,040 5 2 Portugal (PT) 711 34 478 200 Sweden (SE) 1,795 7 39 United Kingdom (UK) 131 1 76 100 Incidence of SAE Number of T&C Country # SAE / 10 000 T&C Processed 0 2 19 processed 0 1 2 3 4 5 6 7 8 9 10 11 12 13 All Reporting Countries 54,832 102 19 Incidence by country Incidence Globally Note: SAE from countries that did not report the number of T&C processed, were not considered. ©2023 EDQM, Council of Europe. All rights reserved. 56 SAE Incidence 2022 SARE exercise (2021 data) Incidence of SAR by Country for Reproductive T&C Incidence of SAE / Incidence of SAE / 10 000 T&C processed Country # Processed # SAE 10 000 T&C 8 processed 7 Belgium (BE) 462,323 33 0.7 7 Bulgaria (BG) 128,270 1 0 Croatia (HR) 51,507 2 0.4 6 Czechia (CZ) 377,585 6 0.2 Denmark (DK) 49,627 24 5 5 870,300 Germany (DE) 5 0 Ireland (IE) 102,932 3 0.3 4 Latvia (LV) 31,780 1 0.3 Netherlands (NL) 245,607 4 0.2 3 Portugal (PT) 10,686 8 7 2 Sweden (SE) 190,052 11 0.6 0.4 1 Incidence of SAE 0 Country Number of T&C # SAE / 10 000 T&C Processed 0 processed 0 1 2 3 4 5 6 7 8 9 10 11 All Reporting Countries 2,520,669 98 0.4 Incidence by Country Incidence Globally Note: SAE from countries that did not report the number of T&C processed, were not considered. ©2023 EDQM, Council of Europe. All rights reserved. 57 SAR and SAE 2022 SARE exercise (2021 data) 268 Total SAR and SAE by Country in 2021 250 200 Total SAE Total SAR 150 100 82 64 53 55 54 53 50 43 42 31 28 24 23 24 25 14 17 13 8 8 11 11 5 5 5 6 6 7 7 3 4 1 1 1 2 1 1 2 2 4 1 5 0 ©2023 EDQM, Council of Europe. All rights reserved. 58  2022 SARE exercise (2021 data) Total SAE by Specification and by Year (2010-2021) 900 217 800 213 700 126 168 156 70 600 190 109 295 Other 119 Human error 500 128 295 357 248 122 System failure 148 145 400 Materials 87 119 53 331 47 189 41 Equipment failure 26 48 300 43 263 55 Tissue/cell defect 148 175 78 39 168 193 200 67 8 91 65 60 290 276 94 81 228 234 254 100 149 82 100 117 121 82 79 47 0 2010 2011 2012 2013 2014 2015 2016 2017 2018 2019 2020 2021 « Materials » specification introduced in 2019 (data from 2018) « System failure » specification introduced in 2020 (data from 2019) ©2023 EDQM, Council of Europe. All rights reserved. 59  2022 SARE exercise (2021 data) Distribution of SAE per specification : 2020 vs 2021 70 Other 213 119 Human error 190 145 System failure 122 41 Materials 47 43 Equipment failure 48 276 Tissue/cell defect 290 0 50 100 150 200 250 300 350 2021 2020 ©2023 EDQM, Council of Europe. All rights reserved. 60 Replacement T&C 2022 SARE exercise (2021 data) Distribution of SAE by Activity Step N=170 Donor selection (15) Other (62) 9% Transport (5) 3% 36% Distribution (7) Procurement (12) 4% 7% Issue (8) Testing (28) 5% 16% Product selection (6) 4% Storage (8) 5% Processing (19) 11% ©2023 EDQM, Council of Europe. All rights reserved. 61 Replacement T&C 2022 SARE exercise (2021 data) Distribution of SAE by Specification N=170 Other (23) 14% Human error (26) 15% Tissue or cell defect (84) 50% System failure (33) 19% Materials (2) Equipment failure (2) 1% 1% ©2023 EDQM, Council of Europe. All rights reserved. 62 Replacement T&C 2022 SARE exercise (2021 data) Distribution of SAE by Activity Step and SAE Type N=170 Tissue or cell defect Equipment failure Materials System failure Human error Other 0 10 20 30 40 50 60 Donor selection 10 3 2 Procurement 5 5 2 Testing 2 1 1 6 18 Processing 11 1 1 3 3 Storage 6 1 1 Product selection 5 1 Issue 7 1 Distribution 1 3 1 2 Transport 3 2 Other 50 2 7 3 ©2023 EDQM, Council of Europe. All rights reserved. 63  2022 SARE exercise (2021 data) Distribution of SAE by Activity Step N=291 Storage (15) 5% Product selection (8) 3% Issue (4) Distribution (5) 1% Processing (100) 2% 34% Transport (7) 2% Other (12) Donor selection (15) 4% 5% Testing (19) 7% Procurement (106) 37% ©2023 EDQM, Council of Europe. All rights reserved. 64  2022 SARE exercise (2021 data) Distribution of SAE by Specification N=291 Human error (14) Other (33) 5% 11% System failure (39) 13% Tissue or cell defect (162) 56% Materials (24) 8% Equipment failure (19) 7% ©2023 EDQM, Council of Europe. All rights reserved. 65  2022 SARE exercise (2021 data) Distribution of SAE by Activity Step and SAE Type N=291 Tissue or cell defect Equipment failure Materials System failure Human error Other 0 20 40 60 80 100 Donor 11 2 2 selection Procurement 78 2 3 14 2 7 Testing 3 3 13 Processing 58 8 10 15 4 5 Storage 7 5 3 Product 7 1 selection Issue 2 2 Distribution 3 11 Transport 3 12 1 Other 2 111 2 5 ©2023 EDQM, Council of Europe. All rights reserved. 66  2022 SARE exercise (2021 data) Distribution of SAE by Activity Step N=233 Donor selection (30) 13% Other (35) Procurement (11) Transport (13) 15% 5% 5% Testing (7) Distribution (7) 3% 3% Issue (7) 3% Product selection (10) Processing (93) 4% Storage (20) 40% 9% ©2023 EDQM, Council of Europe. All rights reserved. 67  2022 SARE exercise (2021 data) Distribution of SAE by Specification N=233 Other (14) 6% Tissue or cell defect (30) 13% Equipment failure (22) 10% Human error (79) 34% Materials (15) 6% System failure (73) 31% ©2023 EDQM, Council of Europe. All rights reserved. 68  2022 SARE exercise (2021 data) Distribution of SAE by Activity Step and SAE Type N=233 Tissue or cell defect Equipment failure Materials System failure Human error Other 0 10 20 30 40 50 60 70 80 90 100 Donor selection 22 2 1 5 Procurement 4 5 2 Testing 5 11 Processing 1 12 5 30 40 5 Storage 6 3 3 7 1 Product selection 6 4 Issue 4 3 Distribution 5 2 Transport 1 4 1 3 3 1 Other 1 2 14 16 2 ©2023 EDQM, Council of Europe. All rights reserved. 69 DISTRIBUTION OF SAE PER SPECIFICATION 2022 SARE exercise (2021 data) • Breaking of bag closure port by employee • The autologous calvaria fell to the ground and had to be discarded (1 piece) • Plate containing the embryo knocked over by operator. The operator indicates that he has • 8.36% (58 out of 694) SAE too little space on the cryowork stations. were reported under the • When transferring the embryos to new culture medium, embryo 2 (not divided) was SAE Specification Human transferred to the new culture plate instead of embryo 3. Embryo 3 was therefore discarded. Error - Other, or no • Mix-up of gametes (no information on partner or non-partner gametes) information to assign • Quarantined gametes were used (no information on partner or donor oocyte) • Gametes stored incorrectly • Inadequate container for transport • Straws incorrectly labelled • Mix-up of donor's names (almost identical) resulting in a mix-up of sperm, and incorrect • A different SAE Specification sperm inseminated could be assigned to each. • Error(s) in hormone treatment - prescription/administration • Handling incidents (excluding falls) • Material fall • Viral screening not in accordance with the legislation • Loss of traceability of 2 embryos • Positive blood cultures in donor (Pseudomonas aeruginosa and Staphylococcus aureus) • Bone piece contaminated by fungi ©2023 EDQM, Council of Europe. All rights reserved. 70 DISTRIBUTION OF SAE PER SPECIFICATION : T/C Defect 2022 SARE exercise (2021 data) • 10% (70 out of 694) SAE were • Bacterial contamination reported under the SAE • Bacterial contamination of direct culture • Microbial contamination of peripheral blood stem cells; results available after Specification Other transplantation • Positive test results • Infection with E. coli in male partner • Incomplete documentation • Positive test results • SAE Specification was not • Positive exudate from implanted bone always assigned accurately. A • Fungal and bacterial contamination of pre-implant medium or tissue different SAE Specification could • Fungal and bacterial contamination of ocular tissue • Splinter in rinsed pocket and aggregates clogging the filter at the end of administration be assigned to each. of graft • Insufficient information provided • Difficulties during graft infusion • First quality control makes a false positive result • Discovery of a genetic disease in a sperm donor • Medical abortion for monosomy 18 and tetralogy of fallot. The IVF was issued from a sperm donation • Organisational failures of the ART procedure ©2023 EDQM, Council of Europe. All rights reserved. 71 DISTRIBUTION OF SAE PER SPECIFICATION : T/C Defect 2022 SARE exercise (2021 data) • 39.76% (276 out of 694) SAE Correct: were reported under the SAE • Unknown genetic factor (non-partner donation) Specification Tissue or Cell • Increased risk of malignancy. A SH2B3 mutation was found in the patient's blood cells Defect after transplantation, originating from the donor. There is no screening for this abnormality. • Release and delivery of a contaminated autologous hematopoietic stem cell unit. An exceptional release was authorized. Preventive antibiotic therapy was instituted in recipient. • Donor was later diagnosed with a partly (multifactorial) hereditary condition • SAE Specification was not Incorrect or potentially incorrect (insufficient information provided): always assigned accurately. • Endproduct (autologous PBSC) contaminated with bacteria • Bacterial contamination of autologous calvaria after aseptic treatment • During preparation the descemet membrane ruptured rendering the tissue unusable for transplantation. • Contamination of embryo culture • Clots and aggregates during automated deplasmation. Manual filtration performed, that produced a high cell leak (cell recovery of 67,5%). • Heart valve without the required characteristics (too small in diameter) • On the day of the graft, the cornea without required characteristic; graft cancelled • Expired cornea ©2023 EDQM, Council of Europe. All rights reserved. 72  2022 SARE exercise (2021 data) Serious Adverse Reactions (in donors) ©2023 EDQM, Council of Europe. All rights reserved. 73 SAR IN DONOR 2022 SARE exercise (2021 data) Voluntary reporting SAR in donor by reporting countries and year 1000 17 17 900 19 19 800 19 21 700 19 17 600 18 500 934 903 846 400 795 700 710 300 620 622 547 200 394 100 104 0 2011 2012 2013 2014 2015 2016 2017 2018 2019 2020 2021 SAR in donor Number of reporting countries ©2023 EDQM, Council of Europe. All rights reserved. 74 SAR IN DONOR 2022 SARE exercise (2021 data) SAR in donor by category of T&C and by country N=1 315 N = 79 300 N = 715 250 200 150 141 100 84 68 50 22 28 24 17 11 17 16 2 2 3 5 6 3 7 5 6 1 6 3 0 2 1 0 Reproductive T&C Haematopoietic Stem Cell Replacement T&C ©2023 EDQM, Council of Europe. All rights reserved. 75 SAR IN DONOR 2022 SARE exercise (2021 data) HSC N= 79 SAR in donors by type of HSC and type of reaction Thrombotic / embolic (11) 7 1 1 2 Reactions other than those listed above (28) 13 3 3 9 Neurological disease (2) 2 Musculoskeletal / joint affection (1) 1 Mechanical damage (from apheresis or bone marrow collection) (9) 6 1 1 1 Infection (8) 1 7 Autoimmune disease (9) 9 Allergic reaction (3) 2 1 Acute systemic toxicity during mobilization or collection (8) 5 3 0 5 10 15 20 25 30 General HSC Autologous Allogenic related Allogenic unrelated ©2023 EDQM, Council of Europe. All rights reserved. 76 SAR IN DONOR 2022 SARE exercise (2021 data) HSC Reactions other than those listed • Hypocalcaemia, anaemia, chest pain not of cardiac or pulmonary aetiology above • Vasovagal reaction with syncope; seminoma; chest pain; upper abdominal pain, vomiting, increased liver enzymes • No mobilization • Lypothimic episode with loss of consciousness during mobilization. Procedure suspended and target not reached • Neoplasm, high haematocrit, product destroyed during transport, donor not starting G-CSF as scheduled • STEMI following donation; patient with CV history • Positive test to COVID-19 in asymptomatic and immunized patient; positive serology test for Hepatitis E in donor before apheresis Acute systemic toxicity during • Ventricular tachycardia during anaesthesia induction mobilization or collection • Various infections, COVID-19 included Infection • Infection Mechanical damage (from apheresis • Catheter site pain, haematoma or bone marrow collection) • Spleen rupture • Inadequate collection • Tissue compromised due to improper bag sealing Thrombotic / embolic • Increase in myocardial necrosis enzymes, hypokinesia of the septal and inferior apex and severe anterior descending artery stenosis • Deep vein thrombosis ©2023 EDQM, Council of Europe. All rights reserved. 77 SAR IN DONOR 2022 SARE exercise (2021 data) Reproductive T&C Tissue Reaction Type Number % Category of SAR Oocytes • OHSS 394 55 • Surgical complications 186 26 • Reactions other than 55 8 above • Infection 51 7 • Torsion of the ovary 29 4 Sperm Surgical complications 2 0 Other o Male genital organ 1 0 reproductive cellulitis tissues ©2023 EDQM, Council of Europe. All rights reserved. 78 SAR IN DONOR 2022 SARE exercise (2021 data) Reproductive T&C N= 712 Distribution of SAR in donors by type of reaction in oocytes Torsion of the ovary (29) 21 8 1 Infections (50) 42 7 Reactions other than above (55) 37 5 13 Surgical Complications (184) 153 26 5 OHSS (394) 352 13 29 0 50 100 150 200 250 300 350 400 450 Partner or autologous Non-partner General ©2023 EDQM, Council of Europe. All rights reserved. 79 SAR IN DONOR 2022 SARE exercise (2021 data) Reproductive T&C Infection Surgical complications Other reactions • Abdominal pain and fever diagnosed • Life-threatening complications • Hematoperitoneum; LPSC surgery as salpingitis and abscess in the left • Hematoperitoneum • Ovariectomy, gravidity after OPU ovary; laparoscopic surgery, abscess • Hemoperitoneum, pelvic • Allergy to medicines, ovariectomy; drainage, antibiotics IV haemorrhage, bladder injury thrombosis; fluidothorax • Infection after OPU • Hemoperitoneum; encapsulated • Anaemia aggravated, dyspnoea, • Ovarian abscess haematoma; urinary retention pulmonary embolism, ectopic • Ovarian & pelvic abscess, turbo- secondary to bladder puncture pregnancy, multiple pregnancy, vagal ovarian abscess, endometritis, • Pelvic peritonitis, Hemoperitoneum, reaction, reversible cerebral pyrexia, haematoma infection, genital vagal injury, ovarian haematoma, vasoconstriction syndrome, deep vein & urinary infection, pyosalpinx, acute lateral popliteal nerve lesion, bladder thrombosis (leg) pyelonephritis, pelvic peritonitis injury, intestinal obstruction • Abdominal pain, tubal pregnancy, • Bladder perforation during oocyte respiratory failure / circulatory instability • Pelvic infection; treatment with antibiotics retrieval • Pulmonary embolus; OHSS post embryo • Bleeding following oocytes aspiration transfer, later hospitalized and • Infected cyst after ovum pick up diagnosed with a PE • Infection • Bleeding, hemoperitoneum, cardiac • Bacterial infection arrest post oocyte retrieval • Pelvic inflammatory disease • Anaphylactic reaction to antibiotic; severe abdominal pain with hospitalization ©2023 EDQM, Council of Europe. All rights reserved. 80 DEATHS IN RECIPIENTS 2022 SARE exercise (2021 data) Haematopoietic Stem Reproductive Country Cells T&C SAR SAE SAR Belgium (BE) 1 Czechia (CZ) 3 France (FR) 10 1 Germany (DE) 1 Poland (PL) 3 Spain (ES) 1 Total = 20 15 1 4 ©2023 EDQM, Council of Europe. All rights reserved. 81 DEATHS IN RECIPIENTS 2022 SARE exercise (2021 data) Hematopoietic Stem Cells N = 16 - 1 death 3 days after allogenic related bone marrow transplant due to cardiogenic shock following myopericarditis FR - 1 death 3 months after autologous PBSCT without identified cause FR - 1 death 15 days after PBSC graft failure and thrombocytopenia complicated by cerebral haemorrhage possibly attributed to graft quality (low viability of cryopreserved CD34+ after thawing) FR* * For the 10 SAR in recipients of hematopoietic stem cell infusions associated with patient demise, France made a general comment indicating that in most cases, imputability is L1 (possible) or L2 (likely, probable) and that death was linked to the clinical condition of patients. It cannot be determined which 10 out of the 43 reported SAR resulted in death. It appears that one fatality was attributed directly to graft quality, but that is unclear as well: death 15 days after PBSC graft failure and thrombocytopenia complicated by cerebral haemorrhage. The imputability is defined as both certain (comment at the end of section SAR -HSC) and possible (comment to section SAE -HSC). It remains unclear which suspected SAE resulted as SAR associated with death. Kind request to MS to provide clarification. ©2023 EDQM, Council of Europe. All rights reserved. 82 DEATHS IN RECIPIENTS 2022 SARE exercise (2021 data) Hematopoietic Stem Cells N = 16 - 1 death four months after the second autologous peripheral blood stem cell transplant (PBSCT) due to septic shock by bacterial translocation and significant immunosuppression (acute digestive GVH and infections post-transplant) imputability to graft quality cannot be fully excluded (previous clinical status of the patient: Lambda IgA multiple myeloma) BE - 1 death after allogenic PBSCT due to multiple organ failure imputability to graft quality cannot be fully excluded (previous clinical status of the patient: severe aplastic anaemia and treatment with ATGAM/CsA/Steroids; haemoculture result negative donor and recipients serologically compatible) DE - 3 SAR: death of recipients within 30 days after PBSCT or during the first hospitalization in connection with the transplant PL ©2023 EDQM, Council of Europe. All rights reserved. 83 DEATHS IN RECIPIENT 2022 SARE exercise (2021 data) Reproductive T & C N=4 • 3 deaths related to IVF (death of offspring) CZ • 1 death related to partner sperm donation; oocyte donor detected as heterozygote carrier (diagnosis of spina bifida on foetus, abortion) ES* • *It is unclear whether death was due to sperm donation or oocyte donor. Kind request to MS to provide clarification. ©2023 EDQM, Council of Europe. All rights reserved. 84  Next steps 2022 SARE exercise (data 2021) FINAL REPORT 2023 SARE exercise (data 2022) Preliminary results [email protected] ©2023 EDQM, Council of Europe. All rights reserved. 85  Thank you for your attention Stay connected with the EDQM EDQM Newsletter: https://go.edqm.eu/Newsletter LinkedIn: https://www.linkedin.com/company/edqm/ Twitter: @edqm_news Facebook: @EDQMCouncilofEurope ©2020 EDQM, Council of Europe. All rights reserved. Saatja: <[email protected]> Saadetud: 14.07.2023 15:17 Adressaat: <[email protected]>; EDQM SARE-TC <[email protected]> Koopia: <[email protected]> Teema: Preliminary results on SARE TC 2022 (2021 data) exercise Dear competent authorities for tissues and cells, Please find attached the preliminary results of the SARE exercise on TC 2022 (data 2021). We would appreciate if you could take a look and provide us your feedback on the data accuracy and the way of its interpretation until 15th August 2023. Please do not hesitate to contact us or directly EDQM (in copy) for any question or doubt. Many thanks and kind regards, The SoHO team. European Commission DG SANTE (Health and Food Safety) Unit D2 Medical Products: quality, safety, innovationOffice address: Rue Breydel 2, 06/004, B-1049 Brussels/Belgium